This is an application for five additional years of support for an ongoing Program-Project. The programmatic organization of our research has greatly facilitated collaborations between basic laboratory scientists and clinical investigators. This approach permits the test in the laboratory, of hypotheses derived from clinical observations, and the early application of laboratory findings to the study of clinical problems. Recently we have developed a novel treatment approach which utilizes the adaptation response of CNS receptors to chronic pharmacological perturbation. We have called this receptor sensitivity modification (RSM). The basic mechanism involved in this adaptational response of receptor cells is being further elaborated and the RSM approach is also being tested as a therapeutic modality in several conditions. A second major effort involves the further development of our findings that prenatal exposure to drugs, stress and other influences has an enduring effect on postnatal receptor and behavioral development in laboratory animals. Further studies of prenatal effects on brain enzymes and biochemistry are underway. These studies may have important implications in the Division of child Psychiatry of our Department to initiate studies of neonatal and older children exposed to neuroleptics in utero. The last aspect of the Program-Project involves studies of possible aberrant enzymes and metabolism in psychiatric subjects. We have paid particular attention to the development of techniques that may make possible the direct study of brain biochemical parameters in human subjects, inasmuch as good animal models of psychosis do not exist. For example, we are attempting to develop new techniques which may improve our ability to use platelet monoamine oxidase (MAO) as a model of brain MAO. We are also studying the mechanisms involved in regulating the activity of catechol-O-methyltransferase, an enzyme importantly involved in biogenic amine function.